Vascular regenerative deficiencies in people with elevated lipoprotein(a): the Lp(a)-VRCE CardioLink-16 translational study.

Aims: Lipoprotein(a) [Lp(a)] is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD); however, the relationship between Lp(a) and the capacity for vascular repair remains unclear. Depletion of vascular regenerative (VR) progenitor cells has been shown to be a novel indicator of compromised vascular repair in people living with cardiometabolic disorders. The purpose of this study was to determine if elevated levels of Lp(a) modify VR cell content properties.

Lp(a) as a Risk Factor for Peripheral Artery Disease: Context Is Everything.

Elevated plasma concentrations of Lp(a) (lipoprotein(a)) are an independent and causal risk factor for the development of atherosclerotic cardiovascular diseases, including peripheral artery disease (PAD). Although proatherosclerotic, proinflammatory, procalcific, and prothrombotic effects have been attributed to Lp(a), the precise pathogenic mechanisms by which Lp(a) contributes to these disorders are unclear. Moreover, whether Lp(a) contributes in different ways to atherosclerotic cardiovascular diseases in different vascular sites has not been explored.

The complex pro-atherosclerotic role of lipoprotein(a): a multiplicity of cellular targets.

Purpose Of Review: Elevated plasma lipoprotein(a) (Lp(a)) is a causal and independent risk factor for atherosclerotic cardiovascular disease; therefore, understanding the fundamental mechanisms underlying Lp(a)-mediated pathogenesis is of significant clinical importance. This review summarizes recent advances in understanding the precise cellular targets of Lp(a) in atherogenesis, uncovering potential therapeutic avenues worth exploring.

Recent Findings: Genetic evidence reveals that Lp(a) is six-fold more atherogenic per particle than LDL, and clinical imaging studies show increased atherosclerotic plaque burden and severity in patients with elevated Lp(a).

Role of Lipoprotein(a) in Atherosclerotic Cardiovascular Disease in South Asian Individuals.

South Asian individuals (SA), representing approximately one quarter of the global population, experience a disproportionately high burden of cardiovascular disease. Some of this increased susceptibility is accounted for by traditional risk factors such as diabetes, hypertension, carbohydrate-rich diets, and rising rates of obesity and metabolic syndrome. However, other previously underappreciated risk factors may also play a crucial role.

Rationale for the Routine Screening of Lipoprotein (a) in Cardiovascular Risk Assessment.

Lipoprotein(a) [Lp(a)] is a lipid particle identified by Mendelian randomization studies to be causally associated with the development of atherosclerotic cardiovascular disease and aortic stenosis, across ethnicities. The risk of cardiovascular disease with markedly elevated Lp(a) is equal to that of untreated familial hypercholesterolemia, and yet, up until now, there has been hesitancy in measuring Lp(a) as a routine part of cardiovascular risk assessment. Screening of Lp(a) level in all individuals is now recommended in the European and Canadian Lipid Guidelines and by the National Lipid Association.

Emerging Implications of Elevated Lipoprotein(a) Levels in Coronary Artery Bypass Graft Surgery.

Background: Coronary artery bypass grafting (CABG) remains a cornerstone in the management of coronary artery disease (CAD). In nonurgent surgical revascularization cases, preoperative optimization of modifiable risk factors can improve outcomes. There is increasing interest in the relationship between lipoprotein(a) levels and the risk for ischemic cardiovascular disease, particularly how CABG outcomes are in turn affected.

Variation in lipoprotein(a) response to potent lipid lowering: The role of apolipoprotein (a) isoform size.

Background: Lipoprotein(a) [Lp(a)] is a driver of residual cardiovascular risk. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) decrease Lp(a) with significant heterogeneity in response. We investigated contributors to the heterogeneous response.

Fibrinogen and plasma clot properties are associated with apolipoprotein B and apolipoprotein B-containing lipoproteins in Africans.

Background: Case-control, intervention and laboratory studies have demonstrated a link between apolipoprotein B (ApoB)-containing lipoproteins and clot structure and thrombosis. There is, however, limited evidence on a population level.

Objectives: We determined the cross-sectional relationship between lipoprotein(a) [Lp(a)], low-density lipoprotein cholesterol (LDL-C), and ApoB with fibrinogen and plasma clot properties in 1462 Black South Africans, a population with higher fibrinogen and Lp(a) levels compared with individuals of European descent.

Lipoprotein(a) and cardiovascular disease.

Elevated plasma levels of lipoprotein(a) (Lp(a)) are a prevalent, independent, and causal risk factor for atherosclerotic cardiovascular disease and calcific aortic valve disease. Lp(a) consists of a lipoprotein particle resembling low density lipoprotein and the covalently-attached glycoprotein apolipoprotein(a) (apo(a)). Novel therapeutics that specifically and potently lower Lp(a) levels are currently in advanced stages of clinical development, including in large, phase 3 cardiovascular outcomes trials.

What's next for lipoprotein(a)? A National Lipid Association report from an Expert Panel Discussion.

This is an exciting time in the lipoprotein(a) [Lp(a)] field. Attention to this important lipoprotein and potent cardiovascular risk marker is transitioning from the purview of the specialist to that of the general practitioner. Its clinical adoption as an important test is increasing in momentum.

Genetics and Pathophysiological Mechanisms of Lipoprotein(a)-Associated Cardiovascular Risk.

Elevated lipoprotein(a) is a genetically transmitted codominant trait that is an independent risk driver for cardiovascular disease. Lipoprotein(a) concentration is heavily influenced by genetic factors, including kringle IV-2 domain size, single-nucleotide polymorphisms, and interleukin-1 genotypes. Apolipoprotein(a) is encoded by the gene and contains 10 subtypes with a variable number of copies of kringle -2, resulting in >40 different apolipoprotein(a) isoform sizes.

Optimization of plasma-based BioID identifies plasminogen as a ligand of ADAMTS13.

ADAMTS13, a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13, regulates the length of Von Willebrand factor (VWF) multimers and their platelet-binding activity. ADAMTS13 is constitutively secreted as an active protease and is not inhibited by circulating protease inhibitors. Therefore, the mechanisms that regulate ADAMTS13 protease activity are unknown.

A focused update to the 2019 NLA scientific statement on use of lipoprotein(a) in clinical practice.

Since the 2019 National Lipid Association (NLA) Scientific Statement on Use of Lipoprotein(a) in Clinical Practice was issued, accumulating epidemiological data have clarified the relationship between lipoprotein(a) [Lp(a)] level and cardiovascular disease risk and risk reduction. Therefore, the NLA developed this focused update to guide clinicians in applying this emerging evidence in clinical practice. We now have sufficient evidence to support the recommendation to measure Lp(a) levels at least once in every adult for risk stratification.

Daring to dream: Targeting lipoprotein(a) as a causal and risk-enhancing factor.

Lipoprotein(a) [Lp(a)], a distinct lipoprotein class, has become a major focus for cardiovascular research. This review is written in light of the recent guideline and consensus statements on Lp(a) and focuses on 1) the causal association between Lp(a) and cardiovascular outcomes, 2) the potential mechanisms by which elevated Lp(a) contributes to cardiovascular diseases, 3) the metabolic insights on the production and clearance of Lp(a) and 4) the current and future therapeutic approaches to lower Lp(a) concentrations. The concentrations of Lp(a) are under strict genetic control.

Lipoprotein(a) induces caspase-1 activation and IL-1 signaling in human macrophages.

Introduction: Lipoprotein(a) (Lp(a)) is an LDL-like particle with an additional apolipoprotein (apo)(a) covalently attached. Elevated levels of circulating Lp(a) are a risk factor for atherosclerosis. A proinflammatory role for Lp(a) has been proposed, but its molecular details are incompletely defined.

Use of Lipoprotein(a) in clinical practice: A biomarker whose time has come. A scientific statement from the National Lipid Association.

Lipoprotein(a) [Lp(a)] is a well-recognized, independent risk factor for atherosclerotic cardiovascular disease, with elevated levels estimated to be prevalent in 20% of the population. Observational and genetic evidence strongly support a causal relationship between high plasma concentrations of Lp(a) and increased risk of atherosclerotic cardiovascular disease-related events, such as myocardial infarction and stroke, and valvular aortic stenosis. In this scientific statement, we review an array of evidence-based considerations for testing of Lp(a) in clinical practice and the utilization of Lp(a) levels to inform treatment strategies in primary and secondary prevention.

PCSK9 deficiency results in a specific shedding of excess LDLR in female mice only: Role of hepatic cholesterol.

PCSK9 promotes the lysosomal degradation of cell surface LDL receptor (LDLR). We analyzed how excess LDLR generated by PCSK9 deficiency is differently handled in male and female mice to possibly unveil the mechanism leading to the lower efficacy of PCSK9 mAb on LDL-cholesterol levels in women. Analysis of intact or ovariectomized PCSK9 knockout (KO) mice supplemented with placebo or 17β-estradiol (E2) demonstrated that female, but not male mice massively shed the soluble ectodomain of the LDLR in the plasma.

Understanding the ins and outs of lipoprotein (a) metabolism.

Purpose Of Review: This review summarizes our current understanding of the processes of apolipoprotein(a) secretion, assembly of the Lp(a) particle and removal of Lp(a) from the circulation. We also identify existing knowledge gaps that need to be addressed in future studies.

Recent Findings: The Lp(a) particle is assembled in two steps: a noncovalent, lysine-dependent interaction of apo(a) with apoB-100 inside hepatocytes, followed by extracellular covalent association between these two molecules to form circulating apo(a).

Oxidized phospholipid modification of lipoprotein(a): Epidemiology, biochemistry and pathophysiology.

Oxidized phospholipids (OxPL) are key mediators of the pro-atherosclerotic effects of oxidized lipoproteins. They are particularly important for the pathogenicity of lipoprotein(a) (Lp(a)), which is the preferred lipoprotein carrier of phosphocholine-containing OxPL in plasma. Indeed, elevated levels of OxPL-apoB, a parameter that almost entirely reflects the OxPL on Lp(a), are a potent risk factor for atherothrombotic diseases as well as calcific aortic valve stenosis.

The long journey of lipoprotein(a) from cardiovascular curiosity to therapeutic target.

Atherosclerosis, as the official journal of the European Atherosclerosis Society (EAS), decided that it would be timely to publish a comprehensive collection of review articles on lipoprotein(a). Spanning the last decade or two, this lipoprotein has become a further target in the fight against atherosclerotic cardiovascular disease. In that time, detailed knowledge about lipoprotein(a) has grown tremendously.

Sortilin enhances secretion of apolipoprotein(a) through effects on apolipoprotein B secretion and promotes uptake of lipoprotein(a).

Elevated plasma lipoprotein(a) (Lp(a)) is an independent, causal risk factor for atherosclerotic cardiovascular disease and calcific aortic valve stenosis. Lp(a) is formed in or on hepatocytes from successive noncovalent and covalent interactions between apo(a) and apoB, although the subcellular location of these interactions and the nature of the apoB-containing particle involved remain unclear. Sortilin, encoded by the SORT1 gene, modulates apoB secretion and LDL clearance.